The investigators of this program seek to design, and synthesize analogs of naturally occurring modified nucleosides of tRNA, and explore their chemotherapeutic usefulness in cancer. Based on the preliminary results, analogs of three classes of modified nucleosides will be prepared: 1. N6-(delta2-isopentenyl) adenosine (IPA), 2. N-(purin-6- ylcarbamoyl)-L-threonine riboside (PCTR), 3. "Compound y" riboside. The analogs will be tested for growth inhibitory activity in cell cultures of RPMI 6410 (derived from human leukemia myeloblasts), L-1210, S-180, NC-37 (normal lymphoblasts) and in a cell line derived from Burkitt lymphoma. The active compounds will be evaluated in vivo in L- 1210 and in TA-3 mammary tumors, and those with promise will be brought to clinical trials. The specific analogs will also be assayed as possible inhibitors of the enzymes adenosine deaminase, xanthine oxidase and adenosine kinase. The mechanism of action and the metabolic fate of the compounds with antineoplastic activity will be studied in tissue culture, animals and in man. The proposal hopes to answer the following questions: (a) What promise do the natural modified nucleosides and their synthetic analogs offer in cancer chemotherapy? (b) What is the mechanism of action of IPA and PCTR analogs in growth inhibition of mammalian cells? Is it possible to block or alter some of the enzymatic processes necessary for the macromolecular synthesis of modified nucleosides? (c) What relationship, if any, does the cytokinin activity of these analogs have to the growth inhibitory activity in the neoplastic (mammalian) cells? What is the mechanism of cytokinin activity? (d) What role do these substances play in cancer biology? Do they serve as regulators of growth and differentiation?